MRI, the most representative tomography technique, is the method to obtain 3-dimensional images non-invasively that has been widely used for the diagnosis of disease owing to its excellent contrast and spatial resolution.
MRI contrast agents are a group of contrast media used to improve the visibility of internal body structures by increasing contrast between normal tissues and abnormal tissues in MRI. MRI contrast agents alter the T1 and T2 relaxation times of tissues and body cavities where they are present. Depending on the image weighting, this can give a higher or lower signal. Most MRI contrast agents work through shortening the relaxation time of protons located nearby. Generally, MRI contrast agents are divided into two groups: paramagnetic contrast agents and superparamagnetic contrast agents (Eur. Radiol. 11: 2319, 2001).
The toxicity of paramagnetic contrast agent is an important concern. It can only produce images at mM level. So, the superparamagnetic contrast agent that can produce high-sensitive images at μM level draws our attention (Nano Lett. 6: 2427, 2006; Nat. Med. 13: 95, 2007).
The superparamagnetic contrast agent widely used in clinical is prepared by using superparamagnetic nanoparticles represented by such superparamagnetic iron oxide (SPIO) as magnetite (Fe3O4) and maghemite (Fe2O3). This agent is prepared as the form of ferrofluid that is stable colloid comprising even particles less than scores of nanometer in size so as to be injected in the body.
The pure superparamagnetic iron oxide particle (1) is hydrophobic and shows the high ratio of volume to surface area, suggesting the strong hydrophobic interaction and coagulation that can form a cluster easily; (2) has low stability, so that the original structure can easily be changed, suggesting that its magnetic characteristics can be easily changed; (3) is easily bio-degraded when it is exposed on so called bio-environment; and (4) does harm on human body because pure iron oxide itself is toxic. Therefore, surface modification of the particle is required to overcome the said problems and to improve stability of ferrofluid containing the superparamagnetic nanoparticles.
For the surface modification, it has been tried to coat the surface with various polymers. As a result, the MRI contrast agents coated with dextran or dextran derivatives have been commercialized. The conventional coating materials are exemplified by such synthetic polymers (J. Mater. Chem. 12: 3654-3659, 2002; J. Colloid Interface Sci. 278: 353-360, 2004) as Polyacrylic acid (PAA), Polyvinylpyrrolidone (PVP), Polyvinylalcohol (PVA), and Polyethylene glycol (PEG); and such natural polymers (J. Colloid Interface Sci. 283: 446-451, 2005; J. Magn. Mater. 293: 20-27, 2005) as Gelatin, Chitosan, and Pullulan, in addition to dextrans.
Mannan is not a material that is widely used. However, it was reported that mannan was used for surface modification (coating) (U.S. Pat. No. 5,262,176; and U.S. Pat. No. 5,462,053). The present inventors had also used mannan previously (Korean Patent No. 10-0949465). U.S. Pat. No. 5,262,176 describes the purpose of use of mannan. In this description, like other conventional polymer coating, the improvement of in vivo stability of iron oxide colloid is the issue. U.S. Pat. No. 5,462,053 also describes the concern about stability of a contrast agent suspension, as the case of other conventional polymer coating. Korean Patent No. 10-0949465 describes the purpose of targeting by a mannose specific receptor, in addition to the generally expected effect of the conventional polymer coating. However, there are problems in the use of mannan, which are biotoxicity and trap in circulation system in vivo. Therefore, it is important to develop a novel mannan derivative that has biocompatibility and low biotoxicity but long half-life in vivo and also to develop a novel MRI contrast agent coated with such mannan derivative.
If specific contrast-enhancement of antigen presenting cells or target tissue that contains a large number of antigen presenting cells by MRI is possible, the clinical usage of it can be definitely increased. In general, cancer tissues or lesion of septic shock has increased number of antigen presenting cells. So, if a large number of antigen presenting cells are detected in a specific area, it suggests that something abnormal is going on. Therefore, it is clinically very important to develop a diagnostic technique to detect any abnormality using the antigen presenting cells.
Numbers of papers and patent descriptions have been cited in this description and the citation is marked in parentheses. The descriptions of cited papers and patent documents are attached in this invention so that the art and text of this invention can be more clearly understood.